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A new pegylated recombinant l-asparaginase (MC0609) was designed to improve pharmacokinetic characteristics and to further reduce immunogenicity in comparison with the currently marketed pegylated Escherichia coli l-asparaginase (pegaspargase, Oncaspar®). Comparative pharmacokinetics (PK), bioavailability, pharmacodynamics and immunogenicity studies were performed in CD® rats and Beagle dogs after intravenous (i.v.) and intramuscular (i.m.) single-dose administration of MC0609 or Oncaspar®. Bioanalytical data on enzymatic activity in serum of animals were used to develop a population pharmacokinetic (PopPK) model to simulate different dosages of MC0609 comparable to the activity time profile of Oncaspar®. In contrast to Oncaspar®, which showed an accelerated elimination over time, a constant serum elimination of enzymatic activity over time was seen for MC0609. Linear PK of MC0609 resulted in a prolonged and dose-dependent duration of enzymatic activity and longer depletion of l-asparagine in peripheral blood. The different PK characteristics of MC0609 and Oncaspar® were confirmed by PopPK analysis and model development. The PK parameters of Oncaspar® in dog scaled to body surface area were in the same range than the parameters determined in paediatric acute lymphoblastic leukaemia patients. Therefore, the dog is considered a clinically relevant model for PK evaluation of Oncaspar®. Distinct differences in immunogenic potential of both preparations were detected after single-dose administration of a therapeutic dose to dogs. An absolute bioavailability of 66 % was calculated for the intramuscular administration of MC0609. The new pegylated recombinant l-asparaginase preparation MC0609 revealed striking differences in PK/PD properties compared with Oncaspar® in rat and dog.

Purpose: Treosulfan (l-threitol-1,4-bis-methanesulfonate, Ovastat) is a prodrug of a bifunctional alkylating agent with activity in ovarian carcinoma and other solid tumors. In a pharmacologic study of the bioavailability of treosulfan in a capsule formulation, patients with relapsed ovarian carcinoma were treated with alternating doses of oral and intravenous (i.v.) treosulfan of 1.5 or 2.0 g daily for 5 to 8 days. Methods: A sensitive method for the determination of treosulfan in plasma and urine by reversed-phase high-performance liquid chromatography had previously been developed. Pharmacokinetic analyses of treosulfan were carried on plasma and urine samples from 20 i.v. courses and 20 courses of oral administration. Results: The bioavailability ratio (f) of oral to i.v. administration was calculated as 0.97 ± 0.18 (mean ± SD) using the values AUCoral=82.1 ± 39.4 μg/ml h and AUCi.v.=85.4 ± 30.3 μg/ml h. The peak plasma concentration cmax (29 ± 14 μg/ml vs 65 ± 23 μg/ml) was significantly (P < 0.01) higher after i.v. administration and the tmax after oral administration was 1.5 ± 0.34 h. The terminal half-life of treosulfan was about 1.8 h. The mean urinary excretion of the parent compound was about 15% of the administered total dose over 24 h (range 6–26%). Conclusions: The high and relatively constant bioavailability of treosulfan indicates that capsules provide a satisfactory noninvasive treatment alternative. A feasible and reliable oral treosulfan formulation could provide the basis for the development of long-term low-dose outpatient treatment of patients with malignant diseases.

Treosulfan (L-threitol- 1,4-bis-methanesulfonate, Ovastat) is a prodrug of a bifunctional alkylating agent with activity in ovarian carcinoma and other solid tumors. For a clinical and pharmacology study, patients with advanced, refractory, or resistant solid tumors were treated with a single-dose intravenous 30-min infusion of 8 or 10 g/m2 treosulfan. A sensitive method for the determination of treosulfan in plasma and urine by reverse-phase high-performance liquid chromatography was developed. A total of 14 plasma and urine treosulfan pharmacokinetics determinations were analyzed in the 8-g/m2 group and 7 were analyzed in the 10-g/m2 group, the maximum tolerated dose for this group of pretreated patients. The terminal half-life of treosulfan was in the range of 1.8 h. AUC and Cmax values were significantly (P < 0.01) higher in the 10-g/m2 group (AUC 708+/-168 versus 977+/-182 microg ml(-1) h, Cmax 465+/-98 versus 597+/-94 microg/ml). The mean urinary excretion of the parent compound was about 25% of the total dose delivered over 48 h (range 5-49%), and about 20% was excreted during the first 6 h after administration. Currently, a clinical phase I pharmacokinetics and dose-escalation trial with autologous blood stem-cell support has been started at 20 g/m2 treosulfan using a 2-h infusion protocol.